A wide variety of bioresorbable or biomedical materials are known that are mostly based on aliphatic polyesters (Uhrich et al. Chem. Rev. 99, 3181-3198, 1999). The mechanical properties of current bioresorbable or biomedical materials are strongly related to their high molecular weights that are in general over 100 kDa, the presence of chemical cross-links, and the presence of crystalline domains in these polymers. Although the crystalline domains are beneficial for the mechanical properties of the material (strength and elasticity), they do have a strong impact on the biodegradation process of the material as the biodegradation of crystalline domains is in general very slow and crystalline domains may cause immunological responses. Moreover, the need for high molecular weight polymers, in order to get the desired material properties, usually implies that high processing temperatures are required, and these are unfavorable as thermal degradation processes become more likely, especially when biologically active species are involved.
There are also several examples of biologically active species that have been covalently attached to polymers for biomedical uses. Especially, oligo-peptide based cell-adhesion promoters such as RGD-sequences have had considerable attention in this respect. RGD-peptides have been covalently attached to a synthetic polymer by copolymerizing RGD-containing monomers, in order to obtain biologically active polynorbornenes (Grubbs et al., J. Am. Chem. Soc. 123, 1275, 2001). Unfortunately, in this way it was only possible to obtain biologically active polynorbornenes, a polymer that is not bioresorbable, and one needs complex chemistry to change the specific biofunctionality. As a result, one is limited in the amount and choice of (combinations) of biologically active molecules. Consequently, this approach lacks freedom in the choice of polymers and bioactivities.
The biologically active RGD-sequence has also been covalently attached to alginates, a naturally occurring polysaccharide (Mooney et al., Biomaterials 20, 45, 1999). The resulting hydrogel materials show enhanced proliferation of myoblast cells. However, specific carbodiimide chemistry is needed to introduce the bioactivity and only materials based on alginates can be used, thereby limiting the mechanical and bioresorbable or biomedical properties of the resulting material. Moreover, polymers from natural sources, such as polysaccharides, are generally costly and may show quality differences when different batches are compared. As the production of synthetic polymers is more controlled, synthetic polymers are preferred because a constant quality can be ensured.
Further known in the art are biomedical coatings that are used to improve the biocompatibility of medical devices. For example, stents may be coated to reduce thrombosis (cf. for example U.S. Pat. No. 6,702,850, incorporated by reference) and implants may be coated to reduce the risks of rejection. Biomedical coatings may further comprise biologically active agents that are released in a controlled manner. Such biomedical coatings may be prepared by mixing a biologically active agent with a polymeric coating formulation.
A biological active agent that has been covalently attached to several polymers for biomedical coatings are heparin-derivatives. For example heparins have been copolymerized in polystyrene and poly(ethylene glycol) systems (Feijen et al., J. Mater. Sci. Mat. Med. 4, 353, 1997), or heparins have been covalently attached to polyurethanes as disclosed in WO98/23307.
These heparin-polymer conjugates are used as anti-thrombogenic coatings for structures to be introduced into living systems. In both cases aromatic diisocyanates are used that are known for their toxic biodegradation profile and a relative low amount of heparin is available at the surface of the coating resulting in a low anti-thrombogenic activity.
Although a strong anchoring of the biologically active molecules to the polymer backbone is preferred in order to guarantee strong cell-adhesion or prolonged bioactivity, there are also materials in which biologically active molecules are only mixed with polymers and are thus not covalently attached to the polymer chain. As a consequence, the biologically active molecules leak out of the material and, therefore, such materials only find uses in drug delivery applications. Examples are hydrogels and microcapsules. Unfortunately, in hydrogels, the rate of drug delivery is hard to tune, while these systems generally suffer from poor material properties. Additionally, the chemical cross-links in their structure limit their biodegradation behaviour. Microcapsules, on the other hand, are prepared from polymers with high glass-transition or melting temperatures, limiting their mechanical performance. Also, microcapsules frequently need bio-incompatible organic solvents to process them.
Another example of non-covalently attached biological active molecules are heparins that are ionically bound to cationic coatings due to heparin's intrinsic negative charge caused by the presence of carboxylates and sulfonates in the molecule, as disclosed for example in U.S. Pat. No. 4,229,838. This method is however rather limited because the bio-active compound is leached over time from the surface due to the relative low ionic binding strength.
Alternatively, hydrophobic interactions have been used to non-covalently attach heparin to polymeric surfaces by end-group functionalizing heparin with an alkyl chain (Matsuda et al., Biomacromolecules, 2, 1169, 2001). However, the hydrophobic interactions are rather poor, resulting in a fast decrease in activity due to leakage of the heparins from the polymeric surfaces.
In general, “supramolecular chemistry” is understood to be the chemistry of non-covalent, oriented, multiple (at least two), co-operative interactions. For instance, a “supramolecular polymer” is an organic compound that has polymeric properties—for example with respect to its rheological behaviour—due to specific and strong secondary interactions between the different molecules. These non-covalent supramolecular interactions contribute substantially to the properties of the resulting material.
Supramolecular polymers comprising (macro)molecules that bear hydrogen bonding units can have polymer properties in bulk and in solution, because of the H-bridges between the molecules. Sijbesma et al. (see WO 98/14504 and Science 278, 1601, 1997) have shown that in cases where the self-complementary quadruple hydrogen unit (4H-unit) is used, the physical interactions between the molecules become so strong that polymers with much better material properties can be prepared.
Several telechelic polymers have been modified with 4H-units before, as has been published in Folmer, B. J. B. et al., Adv. Mater. 12, 874, 2000, and in Hirschberg et al., Macromolecules 32, 2696, 1999. However, these polymers only contain the 4H-unit coupled at the ends of the polymer chains. Consequently, the number of 4H-units in the macromolecule is limited by the amount of end groups to two, and the functional units are always located on the periphery of the polymer, limiting the mechanical properties of the resulting materials.
WO 02/034312 discloses polymers to which heparin is covalently attached.via functional groups.
WO 02/46260 discloses polyurethane based polymers with end capped 4H-bonding units that are optionally grafted with additional 4H-bonding units. The disclosed polymers can be used as hot melt adhesive or TPU-foam. WO 02/98377 discloses a cosmetic composition for care and/or treatment and/or make-up of keratinous materials comprising in a physiologically acceptable medium an efficient amount of a polymer having functional groups that are capable to bind to other functional groups by at least three hydrogen bridges. WO 02/98377 explicitly refers to WO 98/14504 and states that WO 98/14504 does not disclose a cosmetic use of the polymers disclosed therein. WO 02/46260 and WO 02/98377 use comparable or the same chemistry as described in Folmer et al. and Hirschberg et al.
WO 2004/016598, incorporated by reference, discloses chemistry to acquire polymers with grafted quadruple H-bonding units. For example, polyacrylates and polymethacrylates with grafted 4H-units have been produced using different kinds of polymerization techniques. WO 2004/016598 further discloses that these polymers are suitable for applications related to personal care, surface coatings, imaging technologies, biomedical applications, e.g. materials for controlled release of drugs ad materials for tissue engineering and tablet formation, adhesive and sealing compositions, and thickening agents and binders.
WO 2004/052963, incorporated by reference, discloses polysiloxanes comprising 4H-units in the polymer backbone. More precisely, polysiloxanes are disclosed having (a) 4H-units directly incorporated in the polymer backbone, or (b) 4H-units pending from the polymer backbone, wherein the 4H-units are covalently attached via one linker through a silicon-carbon bond. However, the disclosed polymers are not bioresorbable.
Low molecular weight telechelic polycaprolactone endcapped with 4H-units has been described by Dankers et al. (Abstracts of Papers, 225th ACS National Meeting, New Orleans, La., United States, Mar. 23-27, 2003; see PMSE, 88, 52, 2003). It was found that films of this material were biocompatible based on the observed attachment of fibroblast cells to the films. The study on the biodegradation of this polymer showed the presence of crystallites which is not favourable for bioresorption. Moreover, in a paper by ten Cate et al. (Abstracts of Papers, 225th ACS National Meeting, New Orleans, La., United States, Mar. 23-27, 2003; see Polymer Preprints, 2003, 44(1), 618) it was shown that the elasticity of the material was rather poor, as elongations beyond 130% were not possible.
Hence there is a need for versatile supramolecular bioresorbable or biomedical materials that have good and tunable mechanical properties and/or tunable biofunctionality. Additionally, it is desired that these materials are tunable in their biodegradation behavior. Furthermore, it is desired that they can easily be prepared and processed. The present invention addresses these needs by introducing a supramolecular modular approach, wherein different ingredients (or modules or components) are blended—with each module contributing its own specific characteristic (i.e. mechanical performance, bioresorption, bioactivity, etc.)—to produce a material displaying the combined characteristics. This modular approach is usually not easily possible, but is enabled here, as quadruple hydrogen bonding units (4H-units) are used in at least one of the modules that are applied, resulting in contact between the modules in the final material. The presented approach eliminates the need for extensive covalent synthesis, as blending experiments with the various modules can be used to fine-tune the properties of the final material. In addition, every module can be prepared in a controlled way, leading to well defined structures that result in products of controllable high quality.